The Pathobiology of Breast Cancer (eBook)

Jose Russo, MD is Professor and Senior Member of the FCCC. He is Director of the Irma H. Russo, MD-Breast Cancer Research Laboratory and Director of the Breast Cancer and The Environment Research Center at the Fox Chase Cancer Center-Temple Health. Dr, Russo is also Adjunct Professor of Pathology and Cell Biology at Jefferson Medical School and Professor of Biochemistry at Temple Medical School in Philadelphia, Pennsylvania. Dr Jose Russo has authored more than 400 publications; 13 books and is member of several editorial boards of scientific journals. He has received numerous research awards from the National Cancer Institute of the National Institute of Health (NIH) of the United States, from the American Cancer Society and the Department of Defense for his original research in breast cancer.  For the last 35 years he has been an active member of the NIH peer review system and has served as a special reviewer for the American Cancer Society, National Science Foundation, Department of Defense and Veteran Affairs. Dr. Russo has trained 55 Ph.D. and M.D. investigators in cancer research. The interest of Dr. Russo has a broad base, but with a focused goal; 1) to understand the mechanisms that control cancer metastasis and 2) to develop strategies for breast cancer prevention.

Preface 5
Acknowledgments 6
Author’s Bio 7
Contents 8
Chapter 1: The Windows of Susceptibility to Breast Cancer 12
1.1 Introduction 12
1.2 Risk Factor and Etiological Agents 13
1.3 The Concept of the Windows of Susceptibility to Carcinogenesis 16
1.4 The Windows of Susceptibility Apply to Human Breast Cancer 17
1.5 Effect of Hormones on Breast Cancer 20
1.6 Hormones as Carcinogens 20
1.7 Role of Breast Development and Cancer 21
1.8 Fertility and Breast Cancer Risk 23
1.9 Conclusions 24
References 25
Chapter 2: The So Called Pre-Neoplastic Lesions and Carcinoma In Situ 32
2.1 Introduction 32
2.2 The So Called Pre-neoplastic Lesions 32
2.2.1 Ductal Hyperplasia 33
2.2.2 Lobular Hyperplasia 36
2.2.3 Atypical Ductal and Lobular Hyperplasia 36
2.3 The Histopathology of DCIS 40
2.3.1 Comedocarcinoma 41
2.3.2 Papillary Carcinoma in Situ 44
2.3.3 Solid Form of DCIS 45
2.3.4 Cribriform Carcinoma In Situ 45
2.3.5 Micropapillary Carcinoma In Situ 48
2.3.6 Other Forms of DCIS 49
2.4 Lobular Carcinoma In Situ (lClS) 49
2.5 Differential Diagnosis 54
References 54
Chapter 3: The Pathobiology of the Breast Cancer Invasive Process 58
3.1 Introduction 58
3.2 Epithelial Mesenchymal Transition (EMT) 58
3.3 A Human Breast Cancer Cell Model of EMT 60
3.4 Other Factors Involved in the EMT 82
3.5 Conclusions 85
References 86
Chapter 4: The Invasive Breast Cancer Types 89
4.1 Introduction 89
4.2 The Invasive Cancer Subtypes 89
4.2.1 Invasive Ductal Carcinoma No Otherwise Specified (NOS) 90
4.2.2 Invasive Cribriform Carcinoma 102
4.2.3 Mucinous Carcinoma 102
4.2.4 Tubular Carcinoma 106
4.2.5 Medullary Carcinoma 106
4.2.6 Invasive Papillary Carcinoma 106
4.2.7 Apocrine Carcinoma 106
4.2.8 Juvenile (Secretory) Carcinoma 108
4.2.9 Carcinomas with Neuroendocrine Features 110
4.2.10 Metaplastic Carcinoma 110
4.2.11 Inflammatory Carcinoma 111
4.2.12 Paget’s Disease 112
4.2.13 Invasive Lobular Carcinoma 112
4.2.14 Mixed Ductal and Lobular Carcinoma 113
4.3 Microinvasive Breast Carcinoma 116
References 117
Chapter 5: The Molecular Basis of Breast Cancer Subtypes 121
5.1 Introduction 121
5.2 Initial Genomic Classification 121
5.3 Extended Classifications: Molecular Subtypes 122
5.4 The Molecular Taxonomic Breast Cancer International Consortium (METABRIC) Classification 124
5.5 Genomic Classification Based on the Normal Cell Subtype 124
References 126
Chapter 6: Stem Cells in Breast Cancer 127
6.1 Introduction 127
6.2 Cell Markers for Identifying the Stem Cell in the Mammary Gland 128
6.3 Estrogen Receptor as a Marker of Stem Cells in the Mammary Gland 130
6.4 MCF10F Cells Behave as a Stem Cell In Vitro 131
6.5 The MCF-10F in Estrogen Induced Carcinogenesis 133
6.6 The Evidence for the Role of Stem Cells in the Pregnancy Preventive Effect During Carcinogenesis 134
6.7 Isolation of the Stem Cells from the Rat Mammary Gland 136
6.8 Role of the Mammary Gland Stem Cell in the Prevention of Breast Cancer 138
References 139
Chapter 7: The Mechanisms of Breast Cancer Metastasis 145
7.1 Introduction 145
7.2 Route of Metastasis 145
7.3 The Mechanism of Metastasis 146
7.4 The Lymphatic Vessels as a Path for Metastatic Dissemination 147
7.5 The Concept of Stem Cells and Metastasis 149
7.6 Role of Circulating Tumor Cells in Breast Cancer Metastasis 150
7.7 Metastasis of Breast Cancer to Specific Sites 151
7.8 Role of P53 and Metastasis 151
7.9 Problems with the Treatment of Metastasis 152
References 153
Chapter 8: How to Build Up Adequate Prognostic Markers in the Molecular Biology Context of Breast Cancer 159
8.1 Introduction 159
8.2 Tumor Grading 160
8.3 Tumor Grading and Prognosis of Breast Cancer 161
8.4 Characteristics of the Primary Tumor, Such as ER Status, Tumor Size, and Histologic Grade, and Lymph Node Status at the Time of Surgery Served Significantly to Predict the Outcome of the Disease with Regard to Both Recurrence and Patient Survival 169
8.5 ER and PR as Biomarkers of Prognosis 176
8.6 Role of HER2 in Breast Cancer Diagnosis and Treatment 179
8.7 Evaluation of KI67 183
8.8 Molecular Profiling of Breast Cancer 184
8.9 General Considerations 185
References 186
Chapter 9: Preclincial Models for Studying Breast Cancer 192
9.1 Introduction 192
9.2 Xenotransplantation 192
9.2.1 Xenografts for Testing the Tumorigenicity of Chemically Transformed Cells 195
9.2.2 The Oncogene C-HA-RAS Induces a Tumorigenic Phenotype in Human Breast Epithelial Cells 196
9.2.3 Tumorigenicity of 17-?–Estradiol Transformed Human Breast Epithelial Cells 197
9.3 The Labeling of Cancer Cells for an In Vivo Imaging System 197
9.3.1 A Model for Triple Negative Breast Cancer 200
9.4 Development of XtMCF and LmMCF Cell Lines 201
9.4.1 Molecular Characterization of XtMCF and LmMCF Cells 203
9.4.2 XtMCF and LmMCF Cells Are Differed from bsMCF-­luc Cells in Migration, Solid Masses Formation, and Colony Formation Capacity 204
9.4.3 XtMCF and LmMCF Cells Are Highly Tumorigenic and Metastatic In Vivo 205
9.4.4 Classification of Xenografts and Lung Metastases Formed by XtMCF and LmMCF Cells 207
9.4.5 XtMCF and LmMCF Cells Present CD24weak/CD44+/EpCAM+ Cancer Stem Cells Properties, EGF-Like Domain of EpCAM Is Cleaved Off 208
9.4.6 Relevance of the Triple Negative Breast Cancer Model 211
References 214
Chapter 10: Biological Basis of Breast Cancer Prevention 219
10.1 Introduction 219
10.2 Pregnancy as a Physiological Process That Prevent Breast Cancer 219
10.3 Breast Development and Differentiation as the Biological Clue in Cancer Prevention 223
10.4 Basis of the Dual Effect of Late Pregnancy in the Increase Risk of Breast Cancer 227
10.5 Current Strategies in Breast Cancer Prevention 229
10.5.1 Experimental Data Supporting the New Strategy in Prevention 230
10.5.2 Clinical Studies Supporting the New Strategy in Prevention 232
10.5.3 Pregnancy and HCG Induce Permanent Genomic Imprinting or a Specific Signature of Protection 232
10.6 Developing a Prevention Clinical Trial Using HCG 233
10.7 Summary and Conclusions 236
References 237
ERRATUM TO 244